Journal Article

Gender Effect in Experimental Models of Human Medulloblastoma: Does the Estrogen Receptor β Signaling Play a Role?

Travaglia, Daniele, Scambia, Giovanni, Meco, Daniela, Ciucci, Alessandra, De Stefano, Ilaria, Gallo, Daniela, Zannoni, Gian Franco, Mancuso, Mariateresa, Riccardi, Riccardo, Saran, Anna

2014

Overview

The male-to-female sex ratio for medulloblastoma (MB) is approximately 1.5∶1, female gender being also a favorable prognostic factor. This study aimed at evaluating the impact of gender on MB tumorigenesis. In vitro activity of 17β-estradiol (E2), DPN [2,3-bis(4-hydroxyphenyl)-propionitrile, a selective estrogen receptor β (ERβ)-agonist], PPT [4,4',4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, a selective ERα-agonist] or DHT (5 alpha-dihydrotestosterone) was evaluated in three human MB cell lines. D283 Med cells were transplanted into athymic mice. A significant expression of ERβ, with little or no ERα, and low AR (androgen receptor) was found in MB cell lines. The compounds tested did not affect cell proliferation. In vivo, we observed a significantly lower growth of D283 Med in nude female mice compared to males. At microscopic examination, tumors from females showed a shift towards differentiation, as evaluated by lower nestin, and higher NSE (neuron-specific enolase) and GFAP (glial fibrillary acidic protein) expression compared to males. Tumors from females also showed lower Ki67 and p53 expression. The wild-type ERβ protein (ERβ1) was lost in male tumors, while it was a permanent feature in females, and a strong negative correlation was found between Ki67 and ERβ1 expression. Conversely, tumor levels of ERβ2 and ERβ5 did not significantly differ between genders. Increased levels of cyclin-dependent kinase inhibitor p21 were observed in females, suggesting that estrogen may decrease tumor growth through blocking cell cycle progression. An inhibition of the insulin-like growth factor I (IGF-I) signaling was also evident in females. We provides mechanistic evidence supporting the idea that ERβ1 signaling may have pro-differentiation and tumor suppressive function in medulloblastomas.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 17β-Estradiol / Androgen receptors / Animal models / Animals / Apoptosis - drug effects / Biomarkers, Tumor - metabolism / Biotechnology / Brain cancer / Carcinogenesis - drug effects / Carcinogenesis - metabolism / Cell cycle / Cell Cycle - drug effects / Cell growth / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Cerebellar Neoplasms - metabolism / Cerebellar Neoplasms - pathology / Cerebellar Neoplasms - physiopathology / Cyclin-dependent kinase / Cyclin-dependent kinase inhibitor p21 / Differentiation / Dihydrotestosterone / Dihydrotestosterone - pharmacology / Enzyme inhibitors / Estradiol - pharmacology / Estrogen Receptor beta - agonists / Estrogen Receptor beta - metabolism / Estrogens / Female / Females / Gender / Glial fibrillary acidic protein / Hormones / Humans / In vitro methods and tests / Insulin / Insulin-like growth factor I / Male / Males / Medicine and Health Sciences / Medulloblastoma / Medulloblastoma - metabolism / Medulloblastoma - pathology / Medulloblastoma - physiopathology / Mice / Nestin / Neuronal-glial interactions / Nitriles - pharmacology / p53 Protein / Phenols - pharmacology / Phosphopyruvate hydratase / Propionitrile / Pyrazole / Pyrazoles - pharmacology / Sex Characteristics / Sex hormones / Sex ratio / Signal Transduction - drug effects / Signaling / Tumorigenesis / Tumors